tbuckley/cabot-search huggingface dataset:
GARP-mediated active TGF-β1 induces bone marrow NK cell dysfunction in AML patients with early relapse post–allo-HSCT
Authors: Dongyao Wang, Zimin Sun, Xiaoyu Zhu, Xiaohu Zheng, Yonggang Zhou, Yichen Lu, Peidong Yan, Huiru Wang, Huilan Liu, Jing Jin, Huaiping Zhu, Rui Sun, Yi Wang, Binqing Fu, Zhigang Tian, Haiming Wei
Journal: Blood (2022)

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor β1 (TGF-β1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-β1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-β1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-β1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-β1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-β1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.
Genetic control of RNA splicing and its distinct role in complex trait variation
Authors: Ting Qi, Yang Wu, Hailing Fang, Futao Zhang, Shouye Liu, Jian Zeng, Jian Yang
Journal: Nature Genetics (2022)

Abstract Most genetic variants identified from genome-wide association studies (GWAS) in humans are noncoding, indicating their role in gene regulation. Previous studies have shown considerable links of GWAS signals to expression quantitative trait loci (eQTLs) but the links to other genetic regulatory mechanisms, such as splicing QTLs (sQTLs), are underexplored. Here, we introduce an sQTL mapping method, ﻿ t esting for h eterogeneity between is oform-eQ TL e ffects (THISTLE), with improved power over competing methods. Applying THISTLE together with a complementary sQTL mapping strategy to brain transcriptomic ( n = 2,865) and genotype data, we identified 12,794 genes with cis -sQTLs at P &lt; 5 × 10 −8 , approximately 61% of which were distinct from eQTLs. Integrating the sQTL data into GWAS for 12 brain-related complex traits (including diseases), we identified 244 genes associated with the traits through cis -sQTLs, approximately 61% of which could not be discovered using the corresponding eQTL data. Our study demonstrates the distinct role of most sQTLs in the genetic regulation of transcription and complex trait variation.
Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
Authors: Jack M. Fu, F. Kyle Satterstrom, Minshi Peng, Harrison Brand, Ryan L. Collins, Shan Dong, Brie Wamsley, Lambertus Klei, Lily Wang, Stephanie P. Hao, Christine R. Stevens, Caroline Cusick, Mehrtash Babadi, Eric Banks, Brett Collins, Sheila Dodge, Stacey B. Gabriel, Laura Gauthier, Samuel K. Lee, Lindsay Liang, Alicia Ljungdahl, Behrang Mahjani, Laura Sloofman, Andrey N. Smirnov, Mafalda Barbosa, Catalina Betancur, Alfredo Brusco, Brian H. Y. Chung, Edwin H. Cook, Michael L. Cuccaro, Enrico Domenici, Giovanni Battista Ferrero, J. Jay Gargus, Gail E. Herman, Irva Hertz-Picciotto, Patricia Maciel, Dara S. Manoach, Maria Rita Passos-Bueno, Antonio M. Persico, Alessandra Renieri, James S. Sutcliffe, Flora Tassone, Elisabetta Trabetti, Gabriele Campos, Simona Cardaropoli, Diana Carli, Marcus C. Y. Chan, Chiara Fallerini, Elisa Giorgio, Ana Cristina Girardi, Emily Hansen-Kiss, So Lun Lee, Carla Lintas, Yunin Ludena, Rachel Nguyen, Lisa Pavinato, Margaret Pericak-Vance, Isaac N. Pessah, Rebecca J. Schmidt, Moyra Smith, Claudia I. S. Costa, Slavica Trajkova, Jaqueline Y. T. Wang, Mullin H. C. Yu, Branko Aleksic, Mykyta Artomov, Elisa Benetti, Monica Biscaldi-Schafer, Anders D. Børglum, Angel Carracedo, Andreas G. Chiocchetti, Hilary Coon, Ryan N. Doan, Montserrat Fernández-Prieto, Christine M. Freitag, Sherif Gerges, Stephen Guter, David M. Hougaard, Christina M. Hultman, Suma Jacob, Miia Kaartinen, Alexander Kolevzon, Itaru Kushima, Terho Lehtimäki, Caterina Lo Rizzo, Nell Maltman, Marianna Manara, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Norio Ozaki, Aarno Palotie, Mara Parellada, Kaija Puura, Abraham Reichenberg, Sven Sandin, Stephen W. Scherer, Sabine Schlitt, Lauren Schmitt, Katja Schneider-Momm, Paige M. Siper, Pål Suren, John A. Sweeney, Karoline Teufel, Maria del Pilar Trelles, Lauren A. Weiss, Ryan Yuen, David J. Cutler, Silvia De Rubeis, Joseph D. Buxbaum, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Stephan J. Sanders, Michael E. Talkowski
Journal: Nature Genetics (2022)
Clinical management, antiviral drugs and immunotherapeutics for treating monkeypox. An update on current knowledge and futuristic prospects
Authors: Sandip Chakraborty, Deepak Chandran, Ranjan K. Mohapatra, Mahmoud Alagawany, Nahed A. El-Shall, Anil K. Sharma, Chiranjib Chakraborty, Kuldeep Dhama
Journal: International Journal of Surgery (2022)
Sensitivity of anti-SARS-CoV-2 nucleocapsid protein antibody for breakthrough infections during the epidemic of the Omicron variants
Authors: Tetsuya Mizoue, Shohei Yamamoto, Maki Konishi, Yusuke Oshiro, Natsumi Inamura, Takashi Nemoto, Mitsuru Ozeki, Kumi Horii, Kaori Okudera, Haruhito Sugiyama, Nobuyoshi Aoyanagi, Wataru Sugiura, Norio Ohmagari
Journal: Journal of Infection (2022)
EphrinB2 Inhibition and Pembrolizumab in Metastatic Urothelial Carcinoma
Authors: Sarmad Sadeghi, David Quinn, Tanya Dorff, Sumanta Pal, Susan Groshen, Denice Tsao-Wei, Rahul Parikh, Michael Devitt, Mamta Parikh, Alexandra Jackovich, Nora Ruel, Nicholas Vogelzang, Earle Burgess, Imran Siddiqi, Inderbir S. Gill, Primo N. Lara, Robert Dreicer, Parkash S. Gill
Journal: Journal of Clinical Oncology (2022)

Patients with metastatic urothelial carcinoma have poor prognosis after failure of standard first-line chemotherapy. Immune check point programmed death 1-programmed death ligand 1 antibodies have low response rates and thus there exists a major unmet need.In this phase II trial, patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received soluble EphB4-human serum albumin (sEphB4-HSA) in combination with pembrolizumab. The primary end points were tolerability and overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response, and toxicity. The expression of sEphB4-HSA target EphrinB2 was correlated with outcomes.Seventy patients were enrolled. The median follow up was 22.9 months (range, 1.3-54.7). The regimen had acceptable toxicity. In the intent-to-treat analysis (N = 70), the median OS was 14.6 months (95% CI, 9.2 to 21.5). Twenty-six (37%) patients had an objective response (95% CI, 26 to 48). The median PFS was 4.1 (95% CI, 1.5 to 5.7) months. Forty-six (66%) patients expressed EphrinB2, and among them, the median OS was 21.5 months (95% CI, 12.4 to not reached), the ORR was 52% (95% CI, 37 to 67), including a complete response rate of 24% (11 of 46; 95% CI, 12 to 36). The median PFS was 5.7 (95% CI, 2.7 to 27.9) months. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively.The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1/programmed death ligand 1 monotherapy.
Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis
Authors: Tariq E. Farrah, Vanessa Melville, Alicja Czopek, Henry Fok, Lorraine Bruce, Nicholas L. Mills, Matthew A. Bailey, David J. Webb, James W. Dear, Neeraj Dhaun
Journal: Kidney International (2022)

Cardiovascular disease is a complication of systemic inflammatory diseases including anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). The mechanisms of cardiovascular morbidity in AAV are poorly understood, and risk-reduction strategies are lacking. Therefore, in a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in patients with AAV in long-term disease remission and in matched healthy volunteers (32 each group). The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV, and for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A receptor antagonism. Parallel in vitro studies of circulating monocytes and platelets explored mechanisms. Compared to healthy volunteers, patients with AAV had 30% reduced endothelium-dependent vasodilation and 50% reduced acute release of endothelial active tissue plasminogen activator (tPA), both significant in the case-control study. Patients with AAV had significantly increased arterial stiffness (PWV: 7.3 versus 6.4 m/s). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release. Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV in the crossover study. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. Patients with AAV in long-term remission have elevated cardiovascular risk and endothelin-1 contributes to this. Thus, our data support a role for endothelin-blockers to reduce cardiovascular risk by reducing arterial stiffness and increasing circulating tPA activity.
The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs—Therapeutic potential exploration in lung injury
Authors: Juan Pang, Jia Nuo Feng, Wenhua Ling, Tianru Jin
Journal: Acta Pharmaceutica Sinica B (2022)

Since 2005, GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) have been developed as therapeutic agents for type 2 diabetes (T2D). GLP-1R is not only expressed in pancreatic islets but also other organs, especially the lung. However, controversy on extra-pancreatic GLP-1R expression still needs to be further resolved, utilizing different tools including the use of more reliable GLP-1R antibodies in immune-staining and co-immune-staining. Extra-pancreatic expression of GLP-1R has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs, aiming to repurpose them into therapeutic agents for other disorders. Extensive studies have demonstrated promising anti-inflammatory features of GLP-1RAs. Whether those features are directly mediated by GLP-1R expressed in immune cells also remains controversial. Following a brief review on GLP-1 as an incretin hormone and the development of GLP-1RAs as therapeutic agents for T2D, we have summarized our current understanding of the anti-inflammatory features of GLP-1RAs and commented on the controversy on extra-pancreatic GLP-1R expression. The main part of this review is a literature discussion on GLP-1RA utilization in animal models with chronic airway diseases and acute lung injuries, including studies on the combined use of mesenchymal stem cell (MSC) based therapy. This is followed by a brief summary.
Sialic acid-mediated photochemotherapy enhances infiltration of CD8+ T cells from tumor-draining lymph nodes into tumors of immunosenescent mice
Authors: Dezhi Sui, Changzhi Li, Xueying Tang, Xianmin Meng, Junqiang Ding, Qiongfen Yang, Zhaowei Qi, Xinrong Liu, Yihui Deng, Yanzhi Song
Journal: Acta Pharmaceutica Sinica B (2022)

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8+ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8+ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8+ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.
Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications
Authors: Ling Zou, Minru Liao, Yongqi Zhen, Shiou Zhu, Xiya Chen, Jin Zhang, Yue Hao, Bo Liu
Journal: Acta Pharmaceutica Sinica B (2022)

UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
Hepatic Events and Viral Kinetics in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab
Authors: Chiun Hsu, Michel Ducreux, Andrew X. Zhu, Shukui Qin, Masafumi Ikeda, Tae-You Kim, Peter R. Galle, Richard S. Finn, Ethan Chen, Ning Ma, Youyou Hu, Lindong Li, Ann-Lii Cheng
Journal: Liver Cancer (2022)

Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib. Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation. Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab. Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.
Dynamic cell free HPV DNA is an early measure of treatment responsiveness in patients receiving induction chemotherapy for HPV-related head and neck cancer.
Authors: Linda (Yilin) Cao, Ana Ponce Kiess, Michael Hwang, Karim Boudadi, Vassiliki Saloura, Austin Mattox, Emily Gramiccioni, David Schmitt, Jennifer Preston, Anna Malgorzata Starus, Frederick S. Jones, Tanguy Y. Seiwert, Harry Quon
Journal: Journal of Clinical Oncology (2022)

6062 Background: Induction chemotherapy (IC) is being studied as a chemoradiation (CRT) de-intensification strategy in HPV-related head and neck cancer (HNC), but using imaging response for eligibility selection is distinctly limited by delayed correlation with biological response and difficulty in distinguishing active tumor from treatment effect. We report serial cell free HPV DNA (cfHPV DNA) dynamics as a quantitative measure of early treatment responsiveness for HPV-related HNC patients receiving IC followed by CRT. Methods: Patients with high-risk HPV-positive (by in situ hybridization), locally advanced HNC who received IC followed by definitive CRT were enrolled starting on Sept 26, 2021. Patients received 1-2 cycles of platinum/taxane IC prior to initiating standard-dose CRT. Peripheral blood cfHPV DNA levels were measured biweekly during IC and weekly during CRT with the SafeSEQ HPV test from Sysmex Inostics, an NGS-based, CLIA-certified assay designed to sensitively detect and quantify HPV16 and HPV18 DNA in plasma. Tumor volumes were assessed on the pre- and post-IC planning CT scans by the treating radiation oncologist. Results: To date, 72 plasma samples have been processed across 11 enrolled patients with median age 66 years (range: 35-79). The primary disease sites included 7 oropharynx (OPX), 1 sinonasal, 2 nasopharyngeal, and 1 larynx. All patients had at least cT3 disease or cN3 disease (AJCC 8), with 6 patients having cT4 disease. Five (45.5%) have a smoking history, each &gt; 10 pack-years. We report cfHPV DNA and tumor volume measurements at key timepoints for the 8 patients who have completed IC below. Conclusions: Serial cfHPV DNA identifies a group of locally advanced HPV-related HNC patients who have complete/near-complete cfDNA clearance during IC. This may provide an earlier readout of individualized treatment responsiveness compared to radiologic assessment, and may therefore be a preferred metric for CRT de-intensification eligibility. Clearance velocity will be evaluated with our granular biweekly IC and weekly CRT cfHPV DNA dataset to help further elucidate tumor response kinetics with this paradigm. [Table: see text]
Immune-related gene expression signature in patients with recurrent/metastatic head and neck cancer treated with immunotherapy.
Authors: Lisa F. Licitra, Mara Serena Serafini, Federico Pistore, Deborah Lenoci, Mario Airoldi, Maria Cossu Rocca, Primoz Strojan, Cvetka Grasic Kuhar, Marco C. Merlano, Nerina Denaro, Francesco Perri, Athanassios Argiris, Cristina Gurizzan, Federica Perrone, Maria Grazia Ghi, Alessandra Cassano, Giacomo Allegrini, Loris De Cecco, Paolo Bossi
Journal: Journal of Clinical Oncology (2022)

6051 Background: In platinum-resistant recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts), survival improvements have been achieved with immune checkpoint inhibitors (ICI), however this benefit is limited to a relatively small subgroup of pts. Predictive biomarkers are still under investigation and their contribution to the clinic has been limited. An immune-related cluster (Cl6) has been defined by means of a metanalysis in locally advanced HNSCC. Methods: Gene expression profiling was performed on two cohorts of platinum resistant R/M HNSCC pts treated with ICI alone: i) 20 patients as training set, divided in long-term (OS &gt;18 months; n=12) and short-term (OS &lt; 6 months; n=8) survivors matched according to site of recurrence (distant metastases only, or locoregional recurrence with/out metastases); ii) 80 patients enrolled in a phase II trial (EudraCT number: 2017-000562-30; NIVACTOR study) as testing set. The molecular subtyping stratification (De Cecco, Oncotarget 2015) was applied. Subsequently, a score was determined between each sample and the centroids for the 6 clusters previously identified. The threshold point was imputed in the training set as the closest value to the observed prevalence. A Cox multivariable analysis including TMB, CPS and TPS PD-L1 status, age, tumoral subsite and performance status (PS) was performed. Results: Among all the clusters, Cl6 turned out to be significant and applied to training set it provided evidence to discriminate pts’ survivals (AUC=0.86, 95%CI=0.7-1.0; p=2E-05). The stratification based on Cl-6 along with the cut-off point defined in the training set were challenged in the testing set: samples were divided in 28 (35%) having high Cl-6 scores and 52 (65%) with low scores, reaching HR=0.46 (95% CI= 0.27-0.76; p=0.0024). Multivariate analysis showed that only Cl6 (high vs low, HR=0.44; p=0.00443) and PS (1,2 vs 0, HR 1.85; p=0.02686) resulted to be significant on pts’ OS. Conclusions: By analysing two series of pts receiving immunotherapy alone, we identified an immune-related gene expression signature, able to discriminate the prognosis of platinum-resistant R/M HNSCC pts. The multivariate analysis confirmed the immune-related Cl6 as factor linked to outcome in pts treated with immunotherapy, as well as it confirmed the importance of PS. An analysis of the signature on pts receiving first line treatment with immunotherapy is currently ongoing. [Table: see text]